Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules

Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over small molecule inhibitors. We describe dTAG^V-1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12^F36V-tagged proteins. dTAG^V-1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice.